The incidence of esophageal adenocarcinoma is rising faster than for any other cancer in the United States. Esophagogastroduodenoscopy (EGD) is recommended by the American College of Gastroenterology to screen for Barrett's esophagus (BE) in patients with longstanding symptoms of gastroesophageal reflux disease, as BE is a documented risk factor for esophageal adenocarcinoma. Unfortunately, over 95% of esophageal adenocarcinoma develops in previously undiagnosed BE, reflecting the inadequacy of current endoscopic screening efforts. The cost of EGD, associated with the routine use of moderate sedation, may explain why many patients who are appropriate candidates for screening forgo this procedure or are never referred by their primary care providers. Our overall research goal is to develop a low-cost, high quality endoscope capable of screening patients for important esophageal pathology, such as BE. In the last few years, members of our research team have developed an ultrathin flexible catheterscope that is only 1.6 mm in diameter while having a wide field of view (80 degrees). By adding a capsule at the end of the catheterscope to facilitate swallowing, the field of view can be increased to 120 degrees. Since the distal-end components are very low is cost, we can create a flexible esophagoscope that has an insertion end that is single-use and disposable. However, human studies are needed to evaluate the performance of this novel technique. Our first aim is to determine the feasibility of obtaining esophageal images using a tethered capsule endoscope (TCE) and to identify the best protocol for image acquisition. While a prototype TCE has now been has been built and used in a live animal model and one human volunteer, this endoscope has not been studied in humans. Using funding from an American Society for Gastrointestinal Endoscopy Career Development Award (CDA), we will test modifications of the TCE in up to 10 subjects in order to determine how to best get the subjects to swallow the endoscope, and the best protocol for acquiring useful endoscopic images. Once a feasible protocol for the procedure has been determined, we will perform a phase II clinical trial of the TCE. We will recruit 50 subjects (40 funded by this proposal, and 10 funded by the CDA) to undergo endoscopy with the TCE prior to undergoing standard EGD with sedation and compare the findings. Subjects will be queried about their preference for the two procedures. Images obtained via TCE and EGD will be recorded and compared in a blinded fashion by an independent physician. This will allow us to determine if the TCE can obtain adequate images to distinguish BE from normal mucosa. If the TCE is found to be feasible for unsedated esophagoscopy, then funding for a large scale validation study would be sought to determine the accuracy of TCE compared to standard EGD for the detection of esophageal pathology. This has important public health implications since a cost-effective screening tool for BE could help reduce the rising incidence of deaths from esophageal adenocarcinoma.